Pharmaceutical compositions rich in omega-3 (“ω-3” or “n-3”) polyunsaturated fatty acids (“PUFAs”) are being developed to treat a variety of clinical indications.
These products, which are derived from natural sources, typically fish oils, are heterogeneous compositions, and comprise various species of omega-3 PUFAs, omega-6 PUFAs, and other minor components, including mono-unsaturated and saturated fatty acids. The observed clinical effects are typically attributed to the composition as a whole, although the most prevalent of the PUFA species present in the mixture, usually EPA and DHA, are believed to contribute a substantial portion of the observed clinical effect. Because they are heterogeneous compositions, the products are defined to include certain obligate polyunsaturated fatty acid species, each within a defined percentage tolerance range. The compositions are further defined to limit certain undesired components, both those originating in the natural source, such as certain environmental contaminants, and those potentially created in the refining process.
The optimal composition likely differs as among intended clinical indications. Even for the first approved clinical indication, however, treatment of severe hypertriglyceridemia (TGs>500 mg/dl), the optimal composition has not yet been defined.
Thus, the first-approved pharmaceutical composition for treatment of severe hypertriglyceridemia comprises the omega-3 PUFA species eicosapentaenoic acid (“EPA”) and docosahexaenoic acid (“DHA”) in the form of ethyl esters in weight percentages of approximately 46:38 (EPA:DHA), with EPA and DHA together accounting for approximately 84% of all PUFA species in the composition. By contrast, the more recently approved product, Vascepa® (previously known as AMR101), which is approved for the same clinical indication, is >96% pure EPA in the ethyl ester form, with substantially no DHA. The nutraceutical product, OMAX3, sold as a dietary supplement and promoted in part to lower triglyceride levels, comprises EPA and DHA in a weight ratio of about 4.1:1, wherein the EPA and DHA are likewise in the ethyl ester form, the formulation being more than 84% EPA and DHA by weight and more than 90% omega-3 fatty acids by weight.
These wide variations in composition reflect continuing uncertainty as to the optimal composition for this clinical indication.
The uncertainty is due, in part, to competing clinical goals. For example, the omega-3 PUFA species, DHA, is known to be more potent in lowering serum triglycerides than is EPA, but is known to have a greater tendency to increase LDL levels, Mori et al., Am. Nutr. 71:1085-94 (2000), Grimsgaard et al., Am. J. Cln. Nutr. 66:649-59 (1997); elevation of LDL has been thought to be clinically disfavored in subjects with elevated cardiovascular risk. Although decrease in platelet aggregation and thrombogenesis by omega-3 PUFAs is often clinically desired, the potential increase in bleeding time has prompted some to propose adding a certain amount of the omega-6 PUFA species, arachidonic acid (“AA”), to pharmaceutical compositions that are rich in omega-3 PUFAs. See US pre-grant publication no. 2010/0160435.
The difficulty in defining an optimal composition is also due in part to enzymatic interconversion among certain omega-3 PUFA species, and to competition between omega-3 and omega-6 polyunsaturated fatty acids for shared enzymes in their respective biosynthetic pathways from medium chain dietary PUFAs (see FIG. 1).
A further challenge in designing an optimal composition is variation in bioavailability of orally administered PUFA compositions. Absorption of PUFAs in the form of ethyl esters is known, for example, to depend on the presence of pancreatic lipase, which is released in response to ingested fats. Absorption of PUFA ethyl esters is therefore inefficient, and is subject to substantial variation, both among subjects and in any individual subject, depending on dietary intake of fat. See Lawson et al., “Human absorption of fish oil fatty acids as triacylglycerols, free acids, or ethyl esters,” Biochem Biophys Res Commun. 152:328-35 (1988); Lawson et al., Biochem Biophys Res Commun. 156:960-3 (1988). Absorption is particularly reduced in subjects on low-fat diets, a diet advocated for subjects with elevated serum triglyceride levels or cardiovascular disease.
For any specifically desired PUFA pharmaceutical composition, the refining process is designed to produce a final product having the obligate fatty acid components within pre-defined percentage tolerance ranges and to limit certain undesired components to levels below certain pre-defined tolerance limits, with sufficient yield to make the process commercially feasible and environmentally sustainable. Differences in the desired final composition dictate differences in the refining process.
Various known process steps present trade-offs that make composition-specific adaptation and optimization of the refining process difficult, however. For example, urea inclusion complexation (clathration) in the presence of ethanol is often used to remove saturated and mono-unsaturated long chain fatty acids, increasing the relative proportion of desired long chain omega-3 polyunsaturated fatty acids in the resulting composition. Too little urea reduces long chain omega-3 PUFA enrichment. Excess urea, however, can lead to concentration of unwanted components, and has the potential to lead, at any given temperature and reaction time, to increased production of ethyl carbamate, a carcinogen that is impermissible above certain defined low limits. Existing alternatives to urea complexation, however, present other difficulties.
There is, therefore, a need for improved pharmaceutical compositions rich in omega-3 polyunsaturated fatty acids, especially for treatment of hypertriglyceridemia and mixed dyslipidemias, and for improved processes for refining such compositions from fish oil.